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Innovative Biomaterials-Based Solutions

12/04/2012


A variety of developments have been made in biomaterial platform technologies for diverse applications by Ireland’s Network of Excellence for Functional Biomaterials, 
led by Professor Abhay Pandit.

The Network of Excellence for Functional Biomaterials (NFB), based at the National University of Ireland, Galway, was established with the aim of developing the next generation of functional biomaterials. Funding from Science Foundation Ireland (SFI) in 2007 allowed NFB to establish a critical mass of biomaterials activity in Ireland.

NFB is a multidisciplinary group of more than 60 engineers, biologists, chemists and clinicians working together to develop biomimetic materials and platform technologies. These are focused on clinical targets in the areas of musculoskeletal and cardiovascular reconstruction, neural regeneration, soft tissue repair and ophthalmic applications. The researchers are developing new technologies to deliver therapeutic biomolecules such as drugs, genes, cells, growth factors and hormones to specific target sites. NFB uses a wide range of clinically relevant materials. These include naturally occurring polymers súch as collagen, elastin, hyaluronic acid and chitosan; synthetic polymers such as polyethylene glycol (PEG), poly(lactic-co-glycolic acid) (PLGA), poly(lactic acid) (PLA), polyvinyl alcohol (PVA), polydioxanone (PDO) and polycaprolactone (PCL); as well as metals, alloys and ceramics.

NFB’s researchers employ a variety of nano- and micro-fabrication technologies (bottom-up or top-down) to create complex structures with topographical cues to be used as scaffolds for tissue engineering applications. Moreover, state-of-art facilities are available to evaluate the bulk, surface and biological properties of the produced biomaterials.

Biomaterials design has evolved from passive constructs that mimic the structural and mechanical characteristics of native tissues to bioactive constructs that incorporate instructive signals to the scaffold and offer control over cellular functions. To this end, NFB combines natural and synthetic biomaterials that closely imitate native extracellular matrix assemblies with novel functionalisation strategies to improve properties such as mechanical characteristics or efficiency of cellular uptake to modulate cellular functions and facilitate functional neotissue formation (Figure 1). Monofunctional (transglutaminase) and multifunctional polymeric systems (PEG-based) have been designed and developed as means of anchoring therapeutic molecules onto scaffolds. In addition, hollow nano- and microspheres are employed as vehicles for encapsulation and subsequent localised and sustained release of bioactive molecules at the site of the injury.










Figure 1: Three-dimensional constructs functionalisation strategies and clinical targets currently in place at NFB













Intervertebral disc regeneration

One of the NFB’s original targets has been the restoration of degenerated intervertebral discs (IVD). Degeneration of IVD is the main cause of neck and low back pain. The IVD is composed of a gelatinous nucleus pulposus (NP) centre and several surrounding coaxial lamellae that form the inner and outer annulus fibrosus. This unique structural feature allows the IVD to constrain motion at high loads and provide flexibility at low loads. Although factors such as abnormal mechanical stresses, biochemical imbalances and nutritional and genetic deficiencies are all reported to play a role in disc degeneration, the natural ageing process is also characterised by replacement of the gelatinous nucleus pulposus region of the disc by a less-flexible cartilaginous disc. Current treatments (usually massage, mediation, acupuncture and manipulation) typically provide short-term relief though invasive surgery can be used as a last resort.

NFB’s strategy is to develop an injectable, functionalised hydrogel loaded with hollow extracellular matrix-based spheres that will restore the mechanical properties of the disc and deliver genes to upregulate extracellular matrix components such as aggrecan that are limited in the diseased state (Figure 2). The spheres will be functionalised using PEG-based hyperbranched polymers, designed and developed in-house, which will enable delivery of specific bioactive molecules and will be delivered by injection directly into the intervertebral column. The findings of fundamental studies being currently conducted will provide a better understanding of disc degeneration and will be used to develop new therapeutic interventions to treat IVD degeneration.








Figure 2: Schematic for the regeneration of the intervertebral disc











Soft tissue repair

Wound repair results from a complex and highly orchestrated cellular and biochemical response to tissue injury. Given that the wound repair constitutes a major issue in clinical practice with enormous healthcare costs, NFB is developing several scaffold-based platforms to induce wound healing and to restore function. For example, in cases of chronic healing (such as diabetic patients), a fibrin-based scaffold has been used to target a vector encoding eNOS to the wound site. This enhances transfection efficiency of the vector, resulting in greater eNOS expression, greater production of NO and better healing in an impaired wound model.

Recessive dystrophic epidermolysis bullosa (RDEB) is a particularly severe genetic condition that leads to extensive blistering, repeated wounding and poor healing ability. RDEB is caused by mutations in the COL7A1 gene, which results in the reduction or loss of type VII collagen in the skin. One project at NFB aims to deliver the COL7A1 gene encapsulated with a thermal responsive and crosslinkingable hydrogel scaffold to EB cells on the wounds through a non-viral gene-delivery system (Figure 3). NFB is also using natural and synthetic hollow microspheres to encapsulate anti-fibrotic drugs and incorporate them into implantable devices to inhibit fibrotic capsule formation.



Figure 3: Thermo-responsive and chemical cross-linking hydrogel scaffold. (a) Lower critical solution temperature (LCST) behaviour of the copolymer determined by ultraviolet-vis spectrophotometer. Insert: Polymer solution became thermal gel when the temperature was raised above its LCST from 20°C to 37°C, (b) chemical gelation with thiol-functional chemical cross-linker



Another strategy in the area of wound healing is that of cholecyst-derived extracellular matrix (Figure 4). NFB has shown it to be effective in the augmentation of body wall defects primarily because of its strength and inherent biological properties. Optimal stabilisation and functionalisation offers control over degradation that can match the rate of the healing process.




Figure 4: Cholecyst derived extracellular matrix scaffold


Regenerative functional neural constructs
Treatment of spinal cord and peripheral nerve injury is another important clinical target for the group. Transplantation of a variety of cell types has resulted in axon regeneration with some functional improvement after spinal cord injury in animal models, and structural constructs have been shown to aid and direct neurite growth (Figure 5). Molecular therapies that promote regeneration such as administration of neurotrophin, or target deleterious inhibition of regeneration such as chondroitinase ABC, have also yielded favourable results. The multifaceted nature of spinal cord injuries presents a major challenge to therapeutic development, because primary mechanical trauma to the cord induces secondary injury consisting of a complex cascade of molecular events that lead to the loss of myelin and the formation of a glial scar. Despite significant progress in the laboratory, therefore, limited demonstration of functional improvement in in vivo models has prevented regenerative therapies reaching the clinic to date. To devise viable treatment for clinical applications, current work is combining the positive aspects of various current therapeutic approaches.

Figure 5: Neural conduits made of extracellular matrix. (a) Multichannel conduits, (b) neural conduit and (c) neural conduit implanted at site


Regenerative strategies for cardiovascular treatments
Preclinical studies and preliminary data derived from clinical trials indicate the potential for the use of gene therapy or stem cell therapy for cardiovascular applications. At the NFB, the goal is to take gene or stem cell therapy and combine it with biomaterial delivery systems to enhance efficacy and improve control (Figure 6). The clinical targets are ischemic muscle injuries, the first in the myocardium itself (myocardial infarction), and the second is in the lower limb (lower limb ischemia). The choice of gene in the case of biomaterial-mediated gene therapy is also a major focus of the NFB, because novel gene therapy modalities such as miRNA and siRNA knock-down of genes are untested options. The ultimate goal of its cardiovascular group is clinically relevant regeneration or repair after ischemic injury using biomaterial-based therapies.












Figure 6: Schematic of functionalised biomaterials for cardiovascular applications





















NFB is keen to commercialise its growing intellectual property (IP) portfolio for clinical applications in orthopaedics, cardiovascular, neural and soft tissue repair. Professor Pandit, Director of NFB, said, "Our focus is on providing research and development capacities to industry through the development of new products and on adding value to existing products. Galway hosts the highest concentration of medical device companies in Europe. SFI funding has enabled us to engage more directly with the medical device industry and to understand where its needs and the commercial applications for our research efforts lie.”

Technology for license
NFB technology platforms are currently available for licensing:
  • Porous titanium construct for orthopaedic applications
  • Collagen based multi-channel neural conduit
  • Extracellular matrix scaffold for wound closure
  • Hollow core nano-spheres in a range of biodegradable materials
  • PEG-based polymeric linkage systems for linking biomolecules and drugs
  • Injectable PEG based hydrogel system
  • Smart/responsive PEG based dendritic/hyperbranched polymers
  • Degradable pH and reduciable responsive non-viral transfection vectors
  • High grade PLGA and PCL
  • Cell-sheet technologies
  • Various ECM molecules.
NFB’s services to industry include development of unique biomaterial platform technologies, adding value to existing platforms, development of custom–made biomaterials, trouble-shooting biomaterial-based issues in medical devices, and in vitro/in vivo studies.




Dr Stefania Spada is NFB Programme Manager



Dr Dimitrios Zeugolis is NFB Principal Investigator and Lecturer in Biomedical Engineering (Biomaterials)



Dr Wenxin Wang is NFB Principal Investigator and Stokes Lecturer in Biomedical Engineering (Functional Biomaterials)


Professor Abhay Pandit is NFB Director at the Network of Excellence for Functional Biomaterials (NFB), IDA Business Park, Dangan Galway, Ireland,
tel. +353 (0)91 495 833
e-mail: nfb@nuigalway.ie
www.nfb.ie




   

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